Study on the Optimal Dose of Irinotecan for Patients with Heterozygous Uridine Diphosphate-Glucuronosyltransferase 1A1 (UGT1A1).

Uridine 5'-diphospho-glucuronosyltransferase (UGT), a metabolic enzyme of irinotecan active metabolite, has two genetic polymorphisms (UGT1A1*6 and UGT1A1*28). In UGT1A1 homozygous or heterozygous patients, metabolism is delayed and the risk of developing adverse effects is increased, and therefore, dose reduction of irinotecan is considered. However, the specific dose reduction rate of irinotecan for heterozygous patients is uncertain. We studied the necessity of irinotecan dose reduction and its optimal dose in UGT1A1 heterozygous patients with lung cancer. Patients with lung cancer treated with irinotecan in the Tokushima University Hospital or Tokushima Municipal Hospital were included in this study. The dose of irinotecan was evaluated based on the relative dose intensity (RDI). The time to treatment failure (TTF) was defined as the period until treatment change, death, or progressive disease based on response evaluation criteria of solid tumors. We targeted 31 patients treated with irinotecan: 12 wild types (WT), 14 heterozygotes, and 1 complex heterozygote and 4 homozygotes. There was no significant difference in the TTF, but the mean RDI during the entire treatment period was significantly different in the wild type (79%), heterozygous (62%), and complex heterozygous and homozygous groups (46%). In addition, the proportion of patients who completed treatment without dose reduction in the WT group tended to be higher than that in the other groups. For lung cancer patients with UGT1A1 heterozygote types who start irinotecan therapy, reducing the initial dose by approximately 20% might be a safer chemotherapy without decreasing the therapeutic effect.

Comparison of two commercial ELISAs against an in-house ELISA for measuring soluble CD26 in human serum.

BACKGROUND: CD26 is a T-cell costimulatory molecule with dipeptidyl peptidase IV (DPPIV) activity in its extracellular region. The relevance of sCD26 levels and disease activity has been reported in rheumatic or infectious disease. For certain metabolic and endocrine conditions, DPPIV inhibitors were recently developed as a new class of antidiabetic drugs that act by inhibiting DPPIV, the enzyme that inactivates incretin hormone. Higher levels of sCD26 in diabetic patients have been shown to be associated with a poor clinical response to DPPIV inhibitors, with sCD26/DPPIV being an adipokine that may impair insulin sensitivity. With the increasing use of serum sCD26 and DPPIV enzyme activity as biomarkers with potential clinical implications, accurate measurements of serum sCD26 levels and DPPIV enzyme activity are needed. METHODS: We compare two commercially widely available and an in-house enzyme-linked immunosorbent assays (ELISAs) for measurement of serum sCD26 in healthy or diabetic human sera. RESULTS: The significant discrepancies among the results obtained from commercially available and the in-house sCD26 assays were found. We also observed that a linear correlation between serum sCD26 level and DPPIV enzyme activity exists with the in-house ELISA, while the commercial ELISAs demonstrate a lack of consistency between serum sCD26 level and DPPIV enzyme activity. CONCLUSION: These data strongly suggest that new commercial assays for sCD26 plasma levels need detailed evaluation and validation with samples from clinically well-characterized patients, and results obtained from these newer assays should be compared to those obtained from well-established in-house assays such as our assay or other validated sCD26 ELISA assays.

Rice DEP1, encoding a highly cysteine-rich G protein γ subunit, confers cadmium tolerance on yeast cells and plants.

A rice cDNA, OsDEP1, encoding a highly cysteine (Cys)-rich G protein γ subunit, was initially identified as it conferred cadmium (Cd) tolerance on yeast cells. Of the 426 aa constituting OsDEP1, 120 are Cys residues (28.2%), of which 88 are clustered in the C-terminal half region (aa 170-426). To evaluate the independent effects of these two regions, two truncated versions of the OsDEP1-expressing plasmids pOsDEP1(1-169) and pOsDEP1(170-426) were used to examine their effects on yeast Cd tolerance. Although OsDEP1(170-426) conferred a similar level of Cd tolerance as the intact OsDEP1, OsDEP1(1-169) provided no such tolerance, indicating that the tolerance effect is localized to the aa 170-426 C-terminal peptide region. The Cd responses of transgenic Arabidopsis plants constitutively expressing OsDEP1, OsDEP1(1-169) or OsDEP1(170-426), were similar to the observations in yeast cells, with OsDEP1 and OsDEP1(170-426) transgenic plants displaying Cd tolerance but OsDEP1(1-169) plants showing no such tolerance. In addition, a positive correlation between the transcript levels of OsDEP1 or OsDEP1(170-426) in the transgenics and the Cd content of these plants upon Cd application was observed. As several Arabidopsis loss-of-function heterotrimeric G protein ß and γ subunit gene mutants did not show differences in their Cd sensitivity compared with wild-type plants, we propose that the Cys-rich region of OsDEP1 may function directly as a trap for Cd ions.

Predicting risk factors for hypothyroidism after definitive radiotherapy for early glottic carcinomas.

Hypothyroidism may occur after definitive radiotherapy in rare cases of early glottic carcinoma. However, to the best of our knowledge, no study to date has examined the risk factors for hypothyroidism specifically after definitive radiotherapy in patients with early glottic carcinoma. The present study determined risk factors for hypothyroidism after definitive radiotherapy in patients with early glottic carcinoma. This was a retrospective study that included 73 patients with T1 or T2, N0 glottic squamous cell carcinoma who underwent radiotherapy between June 3, 2009 and December 25, 2020. Demographic and clinical characteristics, including age, sex, tumor stage and pretreatment thyroid volume, were examined to elucidate the clinical risk factors for hypothyroidism. Field size, total prescribed dose and thyroid receiving dose were evaluated as dosimetric risk factors for hypothyroidism. Irradiated underlying thyroid volumes of more than 5, 10, 20, 30, 40, 50, 60 and 65 Gy (V5Gy, V10Gy, V20Gy, V30Gy, V40Gy, V50Gy, V60Gy and V65Gy) and mean thyroid dose were included as thyroid receiving doses. The median follow-up duration was 61 months (range, 7-150 months). Hypothyroidism was present in 15 (21%) of the 73 patients, including 12 and 3 patients with grade 1 and 2 hypothyroidism, respectively. Among the demographic and clinical factors, sex and pretreatment thyroid volume were significantly associated with hypothyroidism (P=0.007 and P<0.001, respectively). Among the dosimetric factors, the presence of hypothyroidism was significantly associated with V5Gy (P=0.012), V10Gy (P=0.015), V20Gy (P=0.020), V30Gy (P=0.024), V40Gy (P=0.028), V50Gy (P=0.028), V60Gy (P=0.027) and mean thyroid dose (P=0.023). In conclusion, sex, pretreatment thyroid volume and thyroid receiving dose were associated with hypothyroidism after definitive radiotherapy in patients with early glottic carcinoma. Particularly, the receiving dose to the thyroid gland should be reduced in female patients and in those with small thyroid volumes who are at higher risk for hypothyroidism following radiotherapy.

A multi-ring optical packet and circuit integrated network with optical buffering.

We newly developed a 3 × 3 integrated optical packet and circuit switch-node. Optical buffers and burst-mode erbium-doped fiber amplifiers with the gain flatness are installed in the 3 × 3 switch-node. The optical buffer can prevent packet collisions and decrease packet loss. We constructed a multi-ring optical packet and circuit integrated network testbed connecting two single-ring networks and a client network by the 3 × 3 switch-node. For the first time, we demonstrated 244 km fiber transmission and 5-node hopping of multiplexed 14-wavelength 10 Gbps optical paths and 100 Gbps optical packets encapsulating 10 Gigabit Ethernet frames on the testbed. Error-free (frame error rate < 1 × 10(-4)) operation was achieved with optical packets of various packet lengths. In addition, successful avoidance of packet collisions by optical buffers was confirmed.

Global fast-traveling tsunamis driven by atmospheric Lamb waves on the 2022 Tonga eruption.

On 15 January 2022, the Hunga Tonga-Hunga Ha'apai volcano erupted, producing tsunamis worldwide including first waves which arrived more than 2 hours earlier than what is expected for conventional tsunamis. We investigated the generation and propagation mechanisms of the tsunami "forerunner," and our simulation found that fast-moving atmospheric Lamb waves drove the leading sea height rise whereas the scattering of the leading waves related to bathymetric variations in the Pacific Ocean produced subsequent long-lasting tsunamis. Tsunamis arriving later than the conventionally expected travel time are composed of various waves generated from both moving and static sources, which makes the tsunami, due to this eruption, much more complex and longer-lasting than ordinary earthquake-induced tsunamis.

Predicting factors for primary cervical cancer recurrence after definitive radiation therapy.

OBJECTIVES: The study aimed to retrospectively investigate the apparent diffusion coefficient (ADC) of primary cervical cancer to examine the recurrence correlations in patients treated with radiotherapy (RT). METHODS: The ADC of 31 patients with cervical cancer treated with RT were analyzed as possible risk factors for recurrence. A receiver operating characteristic (ROC) curve of the mean ADC (ADCmean) for the recurrence was generated to determine the cut-off value that yielded optimal sensitivity and specificity. The patient population was subdivided according to the risk factors for recurrence, and the disease-free survival (DFS) was analyzed. The following were investigated to explore the risk factors for recurrence: age, performance status, stage, pelvic lymph node metastasis, histologic tumor grade, maximal diameter of the primary tumor, chemotherapy, and ADCmean. RESULTS: The median follow-up duration of the patients was 25 months. The recurrence was recognized in 9 (29%) of the 31 cases. The ROC analysis of recurrence showed that the area under the ADCmean curve was 0.889 (95% CI, 0.771-1.000; p = 0.001). The cut-off value of ADC mean was 0.900 × 10- 3 mm2/s, with a sensitivity of 86.4% and a specificity of 88.9%. By univariate analysis, the ADCmean was the only factor significantly associated with recurrence. CONCLUSION: The ADCmean of the primary tumor is a potential predictive factor for the recurrence in of cervical cancer. ADVANCES IN KNOWLEDGE: The ADCmean of the primary tumor is a predictor of recurrence in patients with pre-treatment cervical cancer evaluation.

Evaluation of the relationship between the range of radiation-induced lung injury on CT images after IMRT for stage I lung cancer and dosimetric parameters.

BACKGROUND: This study evaluated the correlation between radiation-induced lung injury (RILI) and dosimetric parameters on computed tomography (CT) images of stage I non-small cell lung cancer (NSCLC) patients undergoing intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Sixty-three stage I NSLC patients who underwent IMRT were enrolled in the study. The patients underwent CT within 6 months (acute phase) and 1.5 years (late phase) after radiotherapy. These were fused with the planned irradiation CT. The range of RILI was measured from 10% to 100%, with an IC in 10% increments. RESULTS: The median interval from completion of radiotherapy to acute and late phase CT was 92 and 440 days, respectively. The median RILI ranges of the acute and late phases were in the 80% (20-100%) and 70% dose regions (20-100%), respectively. The significantly narrower range of RILI when lung V20 in the acute phase was less than 19.2% and that of V5 in the late phase was less than 27.6% at the time of treatment planning. CONCLUSIONS: This study showed that RILI occurred in a localized range in stage I NSCLC patients who underwent IMRT. The range of RILI was correlated with V20 in the acute phase and V5 in the late phase. KEY MESSAGES RILI correlated with V20 in acute and V5 in late phase. The shadow of RILI occurred in 80% dose region in acute and 70% in late phase. No relationship exists between radiographic changes in RILI and PTV volume.

Predictive factors for local control of early glottic squamous cell carcinomas after definitive radiotherapy.

The aim of the present study was to retrospectively investigate the risk factors of local failure for T1 glottic carcinoma irradiated with a prescription dose of 66 Gy. Between July 2006 and December 2017, 64 patients with T1 glottic squamous cell carcinoma treated with 66 Gy/33 fractions were analyzed for risk factors of local failure. The sex, age, performance status, T stage, overall treatment time, anterior commissure involvement, smoking status during/after treatment, histological tumor grade and pretreatment hemoglobin level were investigated. The maximum, mean and minimum doses, and the homogeneity index for the glottic larynx were calculated for dosimetric risk factors of local failure. The median follow-up duration was 51 months. Local failure was observed in 6 patients (9.5%). Among all risk factors, only the minimum dose to the glottic larynx was found to be significantly associated with local failure (P=0.025). The 5-year local control rates for a minimum dose to the glottic larynx of <65 and ≥65 Gy were 79 and 95%, respectively, with a statistically significant difference (P=0.015). No patients exhibited grade ≥3 late adverse effects. The minimum dose to the glottic larynx was the only factor significantly associated with local failure. Thus, local control of T1 glottic carcinoma may improve with a minimum dose of ≥65 Gy to the glottic larynx. In conclusion, radiotherapy with a minimum prescription dose of ≥65 Gy to the glottic larynx appears to be safe and achieves a high local control rate for T1 glottic carcinoma.

Prognostic impact of solid tumor component diameter in early-stage non-small cell lung carcinoma treated with intensity-modulated fractionated radiotherapy: a retrospective analysis impact of solid tumor component diameter in NSCLC treated with IMRT.

OBJECTIVE: To investigate the suitability of the new diameter-based subgroupings of the eighth edition Tumor Node Metastasis (TNM) classification system regarding radiotherapy treatment for early-stage non-small-cell lung cancer (NSCLC), we retrospectively re-analyzed the clinical data of patients treated with intensity-modulated radiotherapy using non-coplanar beams (ncIMRT) for Stage I NSCLC. METHODS: Between March 2011 and March 2018, 92 patients with 94 tumors who were diagnosed with Stage I NSCLC according to the seventh edition TNM classification system were enrolled and underwent ncIMRT of 75 Gy in 30 fractions. Local control (LC), progression-free survival (PFS), and overall survival (OS) were retrospectively investigated according to the T-classification subdivisions of the eighth edition and maximal solid tumor component diameter. RESULTS: The median follow-up period was 32.5 months. The median maximum tumor and solid tumor component diameters were 22 mm and 18 mm, respectively. 3-year LC, PFS, and OS rates were 84.1%, 69.4%, and 85.3%, respectively. The 3-year LC rates were 91.0 and 76.8% in the groups with tumor diameter ≤2 cm and >2 cm, corresponding to the T1c and T1b subdivisions of the eighth edition, respectively (p = 0.24). In the ≤2 cm and >2 cm solid tumor component groups, the 3 year LC rates were 93.6 and 63.2%, respectively, which were significantly different (p = 0.007). CONCLUSION: LC rates after radiotherapy in patients with Stage I NSCLC were correlated with solid tumor component diameter. High LC rates in patients with solid tumor components <2 cm in diameter were associated with high PFS and OS rates. ADVANCES IN KNOWLEDGE: This study suggests that the eighth edition TNM classification system, which focuses on solid tumor components rather than tumor diameter, can be applied to radiotherapy.

Phase II study of compensator-based non-coplanar intensity-modulated radiotherapy for Stage I non-small-cell lung cancer.

We conducted a Phase II study to evaluate the usefulness of compensator-based non-coplanar intensity-modulated radiotherapy (ncIMRT) for patients with surgically inaccessible Stage I non-small-cell lung cancer (NSCLC). Patients with pathologically proven or clinically diagnosed surgically inaccessible Stage I NSCLC were enrolled in this study from May 2011 to April 2014. These patients underwent ncIMRT of 75 Gy in 30 fractions regardless of the tumor location. The primary end point was 3-year overall survival, and the secondary end points were local control rate and treatment-related toxicities. A total of 48 patients (50 tumors) were enrolled in this study. Of the 50 tumors, the Stage T1 to T2 ratio was 31 to 19, and the ratio of tumors located in the central to peripheral areas was 11 to 39. During the median follow-up time of 35.9 months, the 3-year actuarial local progression-free and overall survival rates were 82.6% and 87.1%, respectively. No patients experienced toxicities of Grade 3 or greater. Standard-fractionated ncIMRT was effective and safe for patients with surgically inaccessible stage I NSCLC, regardless of the tumor location.

Is severe emphysema, as defined by quantitative CT measurement, a negative risk factor of radiation fibrosis?

OBJECTIVE: To investigate whether patients with emphysema, as evaluated by quantitative CT image measurement, are at risk of developing radiation pneumonitis (RP) after radiotherapy (RT) for non-small cell lung cancer (NSCLC). METHODS: Between March 2011 and June 2015, 68 consecutive patients with Stage I NSCLC treated with a RT dose of 75 Gy given in 30 fractions were enrolled. The median age was 79 years and there were 45 males and 23 females. The number of patients with T1 and T2 were 49 and 19, respectively. The severity of emphysema was evaluated by the percentages of the low attenuation area (LAA) of ≤-860 or -950 Hounsfield unit (HU) and average HU in the whole lung. RESULTS: The mean difference percentages of LAA of ≤-860 (p = 0.0004) or -950 HU (p = 0.005) and average HU (p = 0.001) in patients with RP were significantly lower than those in patients without RP. The area under curve (AUC) of average HU was significantly higher than AUC of LAA of ≤-860 (p < 0.0001) or -950 HU (p < 0.0001). The RP rate after RT was significantly lower when the average HU values were ≤-850 HU (p = 0.0003). CONCLUSION: Patients with emphysema evaluated by average HU (≤-850 HU) in the whole lung were found to be at low risk of RP after RT. Advances in Knowledge: Quantitative measurement of average HU from CT images was predicted of RP after RT.

Predicting risk factors for radiation pneumonitis after stereotactic body radiation therapy for primary or metastatic lung tumours.

OBJECTIVE: To investigate risk factors for radiation-induced pneumonitis (RP) after hypofractionated stereotactic body radiotherapy (SBRT) in patients with lung tumours. METHODS: From May 2004 to January 2016, 66 patients with 71 primary or metastatic lung tumours were treated with SBRT; these 71 cases were retrospectively analyzed for RP. To explore the risk factors for RP, the following factors were investigated: age, sex, performance status, operability, number of treatments, respiratory gating, pulmonary emphysema, tumour location and subclinical interstitial lung disease (ILD). Irradiated underlying lung volumes of more than 5 Gy, 10 Gy, 20 Gy and 30 Gy (Lung V5, V10, V20 and V30), mean lung dose and volumes of gross tumour volume (in cubic centimetre) and planning target volume were calculated for possible risk factors of RP. RESULTS: The median follow-up period was 32 months. RP of Grade 2 or more, according to the Common Terminology Criteria for Adverse Events v. 4.0, was detected in 6 (8.4%) of the 71 cases. Grade 5 RP was identified in two cases. Of the risk factors of RP, subclinical ILD was the only factor significantly associated with the occurrence of RP of Grade 2 or more (p < 0.001). Both cases with Grade 5 RP had ILD with a honeycombing image. CONCLUSION: Subclinical ILD was the only significant factor for Grade 2-5 RP. In addition, the cases with honeycombing had a high potential for fatality related to severe RP. Patients with subclinical ILD should be carefully monitored for the occurrence of severe RP after SBRT. Advances in knowledge: Hypofractionated SBRT for primary or metastatic lung tumours provides a high local control rate and safe treatment.

Factors influencing the durability of the glucose-lowering effect of sitagliptin combined with a sulfonylurea.

We analyzed the changes of glycemic control over 12 months and the factors influencing blood glucose in 162 Japanese patients with type 2 diabetes having inadequate glycemic control despite sulfonylurea-based therapy who received add-on sitagliptin. Hemoglobin A1c (HbA1c) decreased significantly after 4 weeks of treatment, and this improvement was maintained for 1 year, although HbA1c was slightly higher in week 52 than in week 24. Comparison of the patients showing a ≥0.4% increase of HbA1c between weeks 24 and 52 (n = 57) with the others (n = 105) showed a significant difference in the change of bodyweight, as well as the dose of glibenclamide (both P < 0.01). Although combined therapy with sitagliptin and a sulfonylurea seems to be effective for at least 1 year, blood glucose levels are more likely to increase again in patients who show greater weight gain after 24 weeks of treatment and those receiving a higher dose of glibenclamide.

Polyarthropathy in type 2 diabetes patients treated with DPP4 inhibitors.

Dipeptidyl peptidase-4 inhibitors (DPP-4Is) inhibit the inactivation of incretin hormones while also affecting the immune system, since CD26/DPP-4 is involved in immune regulation. The current study shows that the use of DPP-4Is as therapy for type 2 diabetes patients may induce joint symptoms with decrease in plasma SDF-1α level.

Secretory units of islets in transplantation index is a useful clinical marker to evaluate the efficacy of sitagliptin in treatment of type 2 diabetes mellitus.

We carried out a retrospective analysis of 40 Japanese patients with type 2 diabetes mellitus who received sitagliptin. Glycated hemoglobin (HbA1c) and fasting plasma glucose were significantly decreased from 7.53 ± 0.65% and 155.2 ± 29.4 mg/dL at baseline to 6.80 ± 0.60% (P < 0.01) and 131.2 ± 22.3 mg/dL (P < 0.01) at week 20, respectively. ß-Cell function was evaluated by the secretory units of islets in transplantation (SUIT) index, which was significantly increased from 28.5 ± 14.0 at baseline to 38.6 ± 17.0 at week 20 (P < 0.01). Multivariate analysis was carried out between ΔHbA1c and several parameters (age, the duration of diabetes, body mass index, triglyceride [TG], C-peptide [CPR], ΔCPR, HbA1c [baseline] and ΔSUIT), which showed HbA1c (baseline; ß = 0.580, P < 0.001) and ΔSUIT (ß = 0.308, P < 0.05) as significant independent determinants of ΔHbA1c. These two variables explained 53% of the variance in HbA1c response. These results suggest that SUIT index can be a clinical marker for the efficacy of sitagliptin in treatment of diabetes mellitus. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00109.x, 2011).